Basic Concepts of Immunology in Autoimmune Kidney Disease
Ramón G. Bonegio MD, PhDAssociate Chief of Nephrology
Renal Section, Department of MedicineVA-Boston- Healthcare System and
Assistant Professor of MedicineBoston University School of Medicine
Ramon G.B. Bonegio MBBCh, PhD
• University of Witwatersrand School of Health Sciences, South Africa
• Medicine Registrar @Chris Hani Baragwanath and Charlotte MaxekeJohannesburg Academic Hospitals, South Africa
• Nephrology Fellowship @Boston Medical Center
• Assistant Professor of Medicine@ BU– Clinical focus: Glomerular disease– Research focus: Glomerulonephritis and lupus
nephritis
Conflicts of interest
• Dr. Bonegio is or has been the site investigator for clinical trials sponsored by Astra Zeneca, Aurinia pharmaceuticals, Biogen Inc., Genentech and Bristol Myers Squibb
• Dr. Bonegio has received research funding from Pfizer and Merck pharmaceuticals
Introduction
• Introducing the immune system
– Innate immunity
– Adaptive immune cells
• A few new things to be aware of
– Where is the immune system?
– B cell maturation factors
– The plastic T cell subtypes
• A few cases with possible therapeutic implications
• Conclusions
Parts of the immune system
NK cells
Neutrophils
Macrophages
Eosinophils
Basophils
Dendritic
cells
suPAR
ApoL1
Complement
Innate immunity
PRR >>inflammation
B cells
T cells
Antibodies
Adaptive immunity
Antigen-driven >> long-lasting immunity
Cytokines
and
Chemokines
Where is the immune system?
• Gut-associated lymphoid tissue samples antigens from the gut lumen– Critical site of defense
– Critical site tolerance vs effector responses
Ahluwalia et al Scan J. Gastroenterol 2017 and Boston University Histology
Targeted-release formulation (TRF) budesonide ameliorated proteinuria in patients with IgA
nephropathy (NEFIGAN trial)
Fellström et al Lancet 2017
Adaptive immunity: TNF family members regulate the maturation and growth of B cells
MacKay and Browning Nat Rev Immunol 2002
APRIL and IL-6 synergistically activate IgA producing cells to induce aberrant IgA
glycosylation
Makita et al KI 2020
Adaptive immunity: T cell personalities and immune functions
All have TCR
All are antigen driven
Moderate immuneresponses
Enhance immuneresponses
Q1. A 62 year-old woman presents with ANCA-associated RPGN. Which of the following factors IS LEAST LIKELY to contribute to the severity of her glomerular injury?
1) Neutrophils
2) B cells and plasma cells
3) Complement C5a
4) The complement membrane attack
complex (C5b-9)
5) Autoantibodies targeting proteinase 3
or myeloperoxidase
Thanks Joel Henderson
C5aR but not the MAC is requires for crescent formation
Hong Xiao et al. JASN 2014;25:225-231
C5aR-/- C6-/- C5aR-/- with hC5aR
C5aR is requires for neutrophil recruitment to glomeruli and crescent formation
Wild-type
C5aR-/-
Adrian Schreiber et al. JASN 2009;20:289-298
C5aR inhibition in human AAV
David R.W. Jayne et al. JASN 2017;28:2756-2767Phase 3 study currently recruiting – clinical trials.gov NCT02994927
Avacopan + Pred 20
Pred 60
Avacopan only
Q1. A 62 year-old woman presents with ANCA-associated RPGN. Which of the following factors IS LEAST LIKELY contribute to the severity of her glomerular injury?
1) Neutrophils
2) B cells and plasma cells
3) Complement C5a
4) The complement membrane attack
complex (C5b-9)
5) Autoantibodies targeting proteinase 3
or myeloperoxidase
IgG or C1q or C3
Q2. A 24 year-old woman presents with nephrotic range proteinuria and an active urinary sediment. She complains of photosensitivity, hair loss and arthritis
Which of the following are likely targets
that may ameliorate disease
1) The TNF pathways
2) Type 1 interferon pathways
3) C2
4) B cell activation factor (BAFF)
5) CD20+ B cells
Type 1 interferon as a target in SLE
Emily C. Baechler et al. PNAS 2003;100:2610-2615 Lynda Bennett et al. J Exp Med 2003;197:711-723
Adjusted difference in cumulative proportions of patients with herpes zoster - pooled TULIP-1
and TULIP-2 data.
Raj Tummala et al. Lupus Sci Med 2021;8:e000464
©2021 by Lupus Foundation of America
Rituximab in lupus nephritis – LUNAR III
Rovin et al for the LUNAR group Arthritis and Rheumatism 2012
Obinutuzumab - B-cell depletion may work better in SLE patients
Reddy et al, Rheumatology, Volume 56, Issue 7, July 2017
Furie et al 2019 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10).
IgG or C1q or C3
Q2. A 24 year-old woman presents with nephrotic range proteinuria and an active urinary sediment. She complains of photosensitivity, hair loss and arthritis
Which of the following are likely targets
that may ameliorate disease
1) The TNF pathways
2) Type 1 interferon pathways
3) C2
4) B cell activation factor (BAFF)
5) CD20+ B cells Rituximab (case series)
or Obinutuzumab (early studies)
Conclusion• Introducing the immune system
– Innate immunity
– Adaptive immune cells
• A few new things to be aware of– MALT and GALT
– BAFF and APRIL as important B cell maturation regulators
– T cell subtypes
• A few cases with possible therapeutic implications– The role of C5a and the C5aR in AAV
– Targeting specific cell types and cytokine pathways in autoimmune kidney disease
References1. Ahluwalia et al Mucosal Immune System of the Gastrointestinal tract. Scan J. Gastroenterol 2017: 1185-1193
2. MacKay and Browning BAFF: A fundamental survival factor for B cells. Nat Rev Immunol 2002: 465-475
3. Conde et al the Complement System in Flavivirus Infections Front Microbiol 2017: 0213
4. Hong Xiao et al. C5a Receptor (CD88) Blockade Protects against MPO-ANCA. GN: JASN 2014: 225-231
5. Adrian Schreiber et al. C5a Receptor Mediates Neutrophil Activation in ANCA-induced glomerulonephritis. JASN 2009;20:289-298
6. David R.W. Jayne et al. A Ramdomized Trial of C5a Receptor Inhibitor in ANCA-Associated Vasculitis. JASN 2017;28:2756-2767
7. Beck LH Jr et al. M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. N Engl J Med 2009;361:11-21
8. Bruhns et al Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012: 5640-5649
9. Williams, Galdola and Edwards Anti-TNF-indiced lupus. Rheumatology 2009: 716-720
10. Bryans AR and Wu EY Complement Deficiencies in Systemic Lupus Erythematosus. Curr. All. Asthma Rep 2014:448
11. Furie et al Anifrolumab, and Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Lupus Erythematosus. Arthritis and Rheumatol 2016: 376-386
12. Tummala et al Safety profile of anifrolumab in patients with active SLE: and integrated analysis of phase II and III trials
13. Furie et al Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis NEJM 2020: 1117-1128
14. Rovin et al for the LUNAR group Efficacy and Safety of Rituximab in Patients with Active Proliferative Lupus Nephritis: Th Lupus Nephritis Assessment with Rituximab Study. Arthritis and Rheumatism 2012: 1215-1226
15. Reddy et al, Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology m2017: 1227–1237
16. Furie et al 2019 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10).
17. FellstrÖm et al Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial LANCET 2017; 389: 2117-2127
18. Makita et al TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy Kidney Int2020 92(2): 340-349